e2c (r2) step 3 periodic benefit-risk evaluation report ... · table of contents 1 1. ... 3 1.2....

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April 2012 EMA/CHMP/ICH/544553/1998 Committee for medicinal products for human use (CHMP)

ICH guideline E2C (R2) Periodic benefit-risk evaluation report (PBRER) Step 3

Transmission to CHMP 16 April 2012

Adoption by CHMP for release for consultation 16 April 2012

End of consultation (deadline for comments) 21 May 2012

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EC2 (R2) Periodic benefit-risk evaluation report (PBRER) EMA/CHMP/ICH/544553/1998 /41

EC2 (R2) Periodic benefit-risk evaluation report (PBRER)

Table of contents

1. INTRODUCTION ....................................................................................... 4 1

1.1. Background ......................................................................................................... 4 2 1.2. Objectives ........................................................................................................... 5 3 1.3. Scope of the PBRER .............................................................................................. 6 4 1.4. Relation of the PBRER to other ICH documents ........................................................ 6 5

2. GENERAL PRINCIPLES ............................................................................. 7 6

2.1. Single PBRER for an active substance ..................................................................... 7 7 2.2. PBRERs for fixed dose combination product ............................................................. 7 8 2.3. Products manufactured and/or marketed by more than one company ......................... 7 9 2.4. Reference information ........................................................................................... 7 10 2.5. Level of detail within PBRER ................................................................................... 8 11 2.6. Benefit-risk evaluation .......................................................................................... 8 12 2.7. Periodicity and PBRER data lock point ..................................................................... 8 13 2.7.1. International birth date and data lock point .......................................................... 8 14 2.7.2. Managing different frequencies of PBRER submission ............................................. 9 15 2.7.3. PBRERs when periodicity differs across regions .................................................... 10 16 2.7.4. Time interval between data lock point and the submission .................................... 12 17 2.8. Format and presentation of PBRER ....................................................................... 12 18 2.8.1. Format ........................................................................................................... 12 19 2.8.2. Presentation ................................................................................................... 12 20

3. GUIDANCE ON CONTENTS OF THE PBRER .............................................. 14 21

3.1. Introduction....................................................................................................... 15 22 3.2. Worldwide marketing approval status ................................................................... 15 23 3.3. Actions taken in the reporting interval for safety reasons ........................................ 15 24 3.4. Changes to reference safety information ............................................................... 16 25 3.5. Estimated exposure and use patterns ................................................................... 16 26 3.5.1. Cumulative subject exposure in clinical trials ....................................................... 17 27 3.5.2. Cumulative and interval patient exposure from marketing experience .................... 17 28 3.6. Data in summary tabulations ............................................................................... 18 29 3.6.1. Reference information ...................................................................................... 18 30 3.6.2. Cumulative summary tabulations of serious adverse events from clinical trials ........ 19 31 3.6.3. Cumulative and interval summary tabulations from post-marketing data sources .... 19 32 3.7. Summaries of significant safety findings from clinical trials during the reporting period20 33 3.7.1. Completed clinical trials .................................................................................... 20 34 3.7.2. Ongoing clinical trials ....................................................................................... 20 35 3.7.3. Long-term follow-up ........................................................................................ 20 36 3.7.4. Other therapeutic use of medicinal product ......................................................... 20 37 3.7.5. New safety data related to fixed combination therapies ........................................ 20 38 3.8. Findings from non-interventional studies ............................................................... 21 39


3.9. Information from other clinical trials and sources ................................................... 21 40 3.10. Non-clinical data ............................................................................................... 21 41 3.11. Literature ........................................................................................................ 21 42 3.12. Other periodic reports ....................................................................................... 21 43 3.13. Lack of efficacy in controlled clinical trials ............................................................ 22 44 3.14. Late-breaking information.................................................................................. 22 45 3.15. Overview of signals: new, ongoing or closed ........................................................ 22 46 3.16. Signal and risk evaluation .................................................................................. 23 47 3.16.1. Summary of safety concerns ........................................................................... 23 48 3.16.2. Signal evaluation ........................................................................................... 23 49 3.16.3. Evaluation of risks and new information ............................................................ 24 50 3.16.4. Characterisation of risks ................................................................................. 24 51 3.16.5. Effectiveness of risk minimisation (if applicable) ................................................ 25 52 3.17. Benefit evaluation ............................................................................................. 26 53 3.17.1. Important baseline efficacy/effectiveness information ......................................... 26 54 3.17.2. Newly identified information on efficacy/effectiveness ........................................ 26 55 3.17.3. Characterisation of benefits ............................................................................. 26 56 3.18. Integrated benefit-risk analysis for approved Indications ....................................... 27 57 3.18.1. Benefit-risk context - medical need and important alternatives ............................ 27 58 3.18.2. Benefit-risk analysis evaluation ....................................................................... 27 59 3.19. Conclusions and actions .................................................................................... 28 60 3.20. Appendices to the PBRER ................................................................................... 29 61

4. APPENDICES TO THIS GUIDELINE ......................................................... 29 62

APPENDIX A – Glossary ............................................................................................. 30 63 APPENDIX B – Examples of summary tabulations .......................................................... 34 64 APPENDIX C – Tabular summary of safety signals that were new, ongoing or closed during 65 the reporting interval ................................................................................................ 37 66 APPENDIX D – List of PBRER sections, identified as providing cumulative or interval 67 information, and ability to share modules with other regulatory documents ...................... 39 68 APPENDIX E – Examples of possible sources of information that may be used in the 69 preparation of the PBRER ........................................................................................... 41 70


1. INTRODUCTION 71

The Periodic Benefit-Risk Evaluation Report (PBRER) described in this guideline is intended to be a 72 common standard for periodic benefit-risk evaluation reporting on marketed products (including 73 approved drugs that are under further study) among the ICH regions. Regulators from EU, Japan, and 74 the US believe that the PBRER may be used to meet prevailing national and regional requirements for 75 periodic safety and/or benefit-risk reports for approved medicinal products. 76

This guideline defines the recommended content and format of a PBRER and provides an outline of 77 points to be considered in its preparation and submission. 78

Definitions of many technical terms used in the guideline are included in a glossary (Appendix A); the 79 first mention of a term in the guideline is identified with an asterisk (*). 80

1.1. Background 81

When a new medicinal product is approved for marketing, demonstration of safety and efficacy are 82 generally based on data from a limited number of patients, many studied under the controlled 83 conditions of randomised trials. Often, higher risk subgroups and patients with concomitant illnesses 84 that require use of other drugs are excluded from clinical trials, and long-term treatment data are 85 limited. Moreover, patients in trials are closely monitored for evidence of adverse events. In clinical 86 practice, monitoring is less intensive, a broader range of patients are treated (age, co-morbidities, 87 drugs, genetic abnormalities), and events too rare to occur in clinical trials may be observed (e.g., 88 severe liver injury). These factors underlie the need for continuing analysis of relevant safety, 89 efficacy,1 and effectiveness1 information throughout the lifecycle of a medicinal product – promptly, as 90 important findings occur – and periodically, to allow an overall assessment of the accumulating data. 91 Although the majority of new information will be safety-related, new information about effectiveness, 92 limitations of use, alternative treatments, and many other aspects of the drug’s place in therapy may 93 be pertinent to its benefit-risk assessment. 94

The ICH Guideline E2C, Clinical Safety Data Management: Periodic Safety Update Reports for Marketed 95 Drugs, achieved Step 4 in 1996, and was intended to harmonise the periodic reporting requirements to 96 regulatory authorities and to provide, in a common format, the worldwide safety experience of a 97 medicinal product at defined times post-approval. At that time, the focus of the Periodic Safety Update 98 Report (PSUR) was on relevant new safety information in the context of patient exposure, to determine 99 if changes were needed to the product information in order to optimise the use of the product. The 100 guideline was revised in 2003, to provide needed clarification, as well as to provide additional guidance 101 and flexibility. 102

• The pharmacovigilance environment has evolved, however, prompting reassessment of the role of 103 the PSUR in the spectrum of safety documents submitted to regulatory authorities. This 104 reassessment highlighted several factors that led to consensus for revision and refocus of the 105 guideline, to enhance its usefulness in light of advances in the field: 106

• significant progress in the technology and science of pharmacovigilance, including electronic 107 submission of individual case safety reports (ICSRs) to regulatory authorities, automated data 108 mining techniques, and more attention to benefit-risk evaluation; 109

• greater emphasis on proactive and documented risk management planning; 110

1 The terms efficacy and effectiveness are not standardised, and have different meanings in some regions.


• increasing recognition that meaningful evaluation of important new risk information should be 111 undertaken in the context of a medicinal product’s benefits; and 112

• overlap in the content of ICH guidelines related to pharmacovigilance documentation, particularly 113 between ICH guideline E2C, the safety specification component of ICH guideline E2E, and ICH 114 guideline E2F, the Development Safety Update Report (DSUR). 115

As noted above, the primary objective of the PSUR was to provide a comprehensive picture of the 116 safety of approved medicinal products. With recognition that the assessment of the risk of a medicinal 117 product is most meaningful when considered in light of its benefits, the proposed report would provide 118 greater emphasis on benefit than the PSUR, particularly when risk estimates change importantly. In 119 such cases there will need to be an overall explicit evaluation of benefit-risk. Consequently the name 120 of the proposed report is the “Periodic Benefit-Risk Evaluation Report” (PBRER). The PBRER would also 121 provide greater emphasis on the cumulative knowledge regarding a medicinal product, while retaining 122 a focus on new information. 123

A formal evaluation of benefit is a new feature of the PBRER; however, it is recognised that a concise 124 discussion of benefit will usually be sufficient, unless the safety or benefit-risk profile has changed 125 significantly during the reporting interval. Thus, the level of detail provided in certain sections of the 126 PBRER (e.g., evaluation of safety and efficacy data, evaluation of safety signals,* and benefit-risk 127 evaluation) should be proportional to the medicinal product’s known or emerging important risks and 128 to evidence of emerging important benefits. 129

The frequency of submission of reports to regulatory authorities is subject to national or regional 130 regulatory requirements, and may differ, depending on a number of factors. The guideline includes 131 specific advice on managing different frequencies of PBRER submission in different regions. 132

The PBRER has been developed in such a way that the content of particular sections of the report could 133 be identical to that of corresponding sections of other regulatory documents, specifically the safety 134 specification described in the ICH guideline E2E and the DSUR described in ICH guideline E2F. Thus, 135 the content of these sections of the PBRER is envisioned to be suitable for use in the other reports. 136 This “modular approach*” would allow sections or modules to be submitted at different times to 137 multiple authorities, across separate documents (i.e., the PBRER, DSUR, and safety specification). 138 Only modules that include new information would need to be updated when submitting the PBRER. 139 This approach is expected to improve efficiency for marketing authorisation holders (MAHs) and 140 regulatory authorities in their preparation and review of these documents, respectively. 141

1.2. Objectives 142

The main objective of a PBRER is to present a comprehensive and critical analysis of new or emerging 143 information on the risks of the medicinal product, and, where pertinent, on its benefit in approved 144 indications, to enable an appraisal of the product’s overall benefit-risk profile. The PBRER should be 145 submitted to regulatory authorities, and will contain an evaluation of new information relevant to the 146 medicinal product that became available to the MAH during the reporting interval, in the context of 147 cumulative information by: 148

• examining whether the information obtained by the MAH during the reporting interval is in accord 149 with previous knowledge of the medicinal product’s benefit and risk profile; 150

• summarising relevant new safety information that could have an impact on the benefit-risk profile 151 of the medicinal product; 152


• summarising any important new efficacy/effectiveness information that has become available 153 during the reporting interval; and 154

• where important new safety information has emerged, conducting an integrated benefit-risk 155 evaluation for approved indications. 156

When desired by the MAH, a list of the sources of information used to prepare the PBRER can be 157 provided as an appendix to the report.2 158

A PBRER should be concise and provide sufficient information to assure regulatory authorities that the 159 MAH is adequately monitoring and evaluating the evolving risk profile of a medicinal product. All 160 pertinent new safety information discovered during the reporting interval3 should be discussed in the 161 appropriate sections of the PBRER. Urgent safety information should be reported through the 162 appropriate mechanism; the report is not intended to be used to provide initial notification of 163 significant new safety information or to provide the means by which new safety concerns* are 164 detected. 165

1.3. Scope of the PBRER 166

The main focus of each PBRER is the evaluation of relevant new safety information from the available 167 data sources,3 placed within the context of any pertinent efficacy/effectiveness information that may 168 have become available since the International Birth Date (IBD), the date of the first marketing 169 approval in any country in the world, or the Development International Birth Date (DIBD), the date of 170 first authorisation for the conduct of an interventional clinical trial in any country.4 The PBRER should 171 include cumulative knowledge of the product while retaining focus on new information, i.e., the overall 172 safety evaluation and integrated benefit-risk evaluation will take into account cumulative information. 173 Because clinical development of a drug frequently continues following marketing approval, relevant 174 information from post-marketing studies or clinical trials in unapproved indications or populations 175 should also be included in the PBRER. Similarly, as knowledge of the safety of a medicinal product 176 may be derived from evaluation of data associated with uses other than the approved indication(s), 177 such knowledge would be reflected in the risk evaluation, where relevant and appropriate. 178

The PBRER should provide summaries of significant safety, efficacy/effectiveness information from data 179 sources available to the MAH, when relevant to the benefit-risk evaluation. 180

1.4. Relation of the PBRER to other ICH documents 181

At present, some ICH countries and regions accept submission of separate types of periodic reports to 182 fulfil national and regional requirements within the post-approval period: the PSUR (ICH guideline 183 E2C(R1)) for periodic reporting of the safety of approved medicinal products, the DSUR (ICH guideline 184 E2F) for periodic reporting on the safety of medicinal products that remain in clinical development, and 185 the safety specification component of ICH guideline E2E that might be submitted at the time of 186 marketing application and/or PSUR submission to aid in the planning of pharmacovigilance activities. 187 As these documents have different regulatory purposes, different periodicities, and can be reviewed by 188 different divisions within a single regulatory authority, each document needs to be complete in its own 189

2 Examples of potential sources of information to be used in preparation of a PBRER will be included in the Step 4 guideline as general guidance. 3 This guideline should not serve to limit the scope of information to be provided in the evaluation of benefit-risk of a medicinal product. Please refer to the applicable laws and regulations in the countries and regions in which the PBRER is to be submitted. 4 For the purpose of this document, the terms “authorisation” and “authorised” refer to clinical trials and the terms “approval” and “approved” refer to marketing applications.


right – a comprehensive document that can stand alone. Nevertheless, overlap and repetition between 190 the content of the DSUR, PSUR, and safety specification can lead to inefficiencies – both in the 191 production of the documents by the MAH, and in the review of the documents by regulatory 192 authorities. This guideline aims to address this duplication and facilitate flexibility by encouraging the 193 use of individual modules, where they pertain to more than one report – to be used at different times, 194 for different authorities, and for different purposes. Therefore, the PBRER has been developed in such 195 a way that content of several sections may be used for sections of other documents as a basis for a 196 modular approach (see Section 1.1). 197

2. GENERAL PRINCIPLES 198

2.1. Single PBRER for an active substance 199

The PBRER should provide information on all approved indications, dosage forms, and regimens for the 200 active substance, with a single data lock point. In some circumstances, it will be appropriate to 201 present data by indication, dosage form, dosing regimen, or population (e.g., children vs. adults) 202 within the relevant section(s) of the PBRER. In exceptional cases, submission of separate PBRERs 203 might be appropriate, for example, an active substance used in two formulations for systemic and 204 topical administration in entirely different indications. In these cases, the regulatory authorities should 205 be notified and their agreement obtained, preferably at the time of approval. 206

2.2. PBRERs for fixed dose combination product 207

For combinations of substances also marketed individually, information for the fixed combination may 208 be reported either in a separate PBRER or included as separate presentations in the report for one of 209 the individual substances, depending on the circumstances. Cross-referencing all relevant PBRERs is 210 considered important. 211

2.3. Products manufactured and/or marketed by more than one company 212

Each MAH is responsible for submitting PBRERs for its own products. 213

When companies are involved in contractual relationships (e.g., licensor-licensee), respective 214 responsibilities for preparation and submission of the PBRER to the regulatory authorities should be 215 clearly specified in the written agreement. 216

When data received from a partner company(ies) might contribute meaningfully to the safety and/or 217 benefit-risk analyses and influence the reporting company’s product information, these data should be 218 included and discussed in the PBRER. 219

2.4. Reference information 220

An objective of a PBRER is to evaluate whether information obtained during the reporting interval is in 221 accord with previous knowledge on the product’s benefit and risk, and to indicate whether changes 222 should be made to product information. Reference information is needed to perform this comparison. 223 Having one reference source of information in common for the three ICH regions would facilitate a 224 practical, efficient, and consistent approach to the safety evaluation and make the PBRER a unique 225 report accepted in all countries and regions. 226

It is a common practice for MAHs to prepare their own “Company Core Data Sheet,*” CCDS, which 227 covers material relating to safety, indications, dosing, pharmacology, and other information concerning 228


the medicinal product. The core safety information contained within the CCDS is referred to as the 229 “Company Core Safety Information,*” CCSI. The latest CCDS in effect at the end of the reporting 230 interval should be used as the reference for both the benefit and risk sections of the PBRER. The 231 national or regional approved product information, which can differ from the CCDS, continues to be the 232 reference document upon which labeledness/expectedness is based for the purpose of national or 233 regional expedited post-marketing safety reporting. 234

It is important to highlight any differences between the CCSI and the national or regional product 235 information/labelling in the cover letter or a regional appendix accompanying submission of the PBRER. 236

The MAH should continuously evaluate whether any revision of CCDS/CCSI is needed whenever new 237 safety information is obtained throughout the reporting interval. All changes to the CCDS/CCSI made 238 during the interval should be described in Section 4 (“Changes to Reference Safety Information*”) 239 and/or Section 16 (“Signal and Risk Evaluation”) of the PBRER. The MAH should provide a copy of the 240 current version of the CCDS(s) referred to in the PBRER as an appendix to the report. 241

2.5. Level of detail within PBRER 242

The level of detail provided in certain sections of the PBRER should depend on the medicinal product’s 243 known or emerging important benefits and risks. This approach is applicable to those sections of the 244 PBRER in which there is evaluation of safety data, efficacy/effectiveness data, safety signals, and 245 benefit-risk. Therefore, the extent of information provided in such PBRER sections will vary among 246 individual PBRERs. 247

For example, when there is important new safety information, a detailed presentation of that 248 information should be included, plus any other relevant contextual information (e.g., updated full 249 benefit information) needed to facilitate a robust benefit-risk analysis. Conversely, when little new 250 important safety information has become available during the reporting interval, a concise summary of 251 baseline benefit information should be sufficient, and the benefit-risk evaluation would consist 252 primarily of an evaluation of updated interval safety data, with the recognition that the benefit-risk 253 profile has not changed during the reporting interval. 254

2.6. Benefit-risk evaluation 255

When a drug is approved for marketing, a conclusion has been reached that, when used in accordance 256 with approved product information, its benefits outweigh its risks. As new information about the drug 257 emerges during marketing experience, benefit-risk evaluation should be carried out to determine 258 whether benefits continue to outweigh risks, and to consider whether steps need to be taken to 259 improve the benefit-risk relationship through risk minimisation activities,* e.g., labelling changes, 260 communications with prescribers, or other steps. 261

This assessment may include evaluation of populations and/or endpoints that were not investigated in 262 the registrational clinical trials. 263

2.7. Periodicity and PBRER data lock point 264

2.7.1. International birth date and data lock point 265

The date of the first marketing approval for the medicinal product in any country in the world is the 266 IBD. For medicinal products that are on the market in many countries, it is possible that there are 267 several national or regional birthdates. Such different birthdates should be harmonised with the IBD 268


with agreement of regulatory authorities. Through PBRERs prepared with harmonised IBDs, the same 269 updated safety and benefit-risk information can be reviewed globally by all regulatory authorities. 270

The data lock point is the date designated as the cut-off for data to be included in a PBRER, based on 271 the IBD. For administrative convenience, if desired by the MAH, the data lock point of the PBRER can 272 be designated as the last day of the month of the end of the reporting interval, with a corresponding 273 change to the start date of the next reporting interval. When a report contains information on different 274 dosage forms, formulations, or uses (indications, routes and/or populations), which might be approved 275 at different times, the original IBD should be maintained to determine the data lock point for purposes 276 of the unified PBRER. 277

When clinical development of a medicinal product continues following marketing approval, the starting 278 point of the DSUR reporting interval can be synchronized with the IBD-based cycle, so that both the 279 DSUR and PBRER can be prepared at the same time. 280

2.7.2. Managing different frequencies of PBRER submission 281

The need for the submission of a PBRER and the frequency of report submission to regulatory 282 authorities are subject to national or regional regulatory requirements, and usually depend on such 283 factors as the length of time the product has been on the market and the extent of knowledge of the 284 benefit-risk profile of the product. During the initial years of marketing of new molecular entities 285 (NMEs), reports will generally be requested more frequently (i.e., 6-monthly or annually). Once a drug 286 has been marketed for several years, national or regional regulation may allow the frequency of 287 submission to be extended to longer time intervals; however, more frequent PBRERs may continue to 288 be required in other regions. As a result, the following circumstances give some indication of the 289 various scenarios that may be encountered by MAHs: 290

• Because approval dates and/or reporting frequency requirements differ across regions, PBRERs 291 may be required on 6-monthly, annual, and less frequent submission timetables simultaneously 292 across many regions. 293

• In some countries or regions, for products considered to have an established and acceptable safety 294 profile or considered to be low risk, the frequency of reporting may be reduced, or the need to 295 submit periodic reports may be eliminated completely. Even in such cases, where PBRERs are no 296 longer required to be submitted, it is expected that MAH’s will continue to evaluate the safety of 297 their products on a regular basis and report any new safety information that impacts on the 298 benefit-risk profile or the labelling of the product. 299

• Changes in reporting frequency may also apply after important additions or changes in clinical use 300 are approved (e.g., new indication[s] and/or new population[s]), if such changes are regarded as 301 having the potential to impact the benefit-risk profile of the product. In these circumstances, it is 302 possible that the reporting interval will be shortened, even for older products with a previously 303 reduced frequency of PBRER submission. 304

• An ad hoc PBRER may be requested by a regulatory authority (see Section 2.7.3.2 of this 305 guideline) 306

As a result, the MAH may need to prepare PBRERs covering different intervals for different regulatory 307 authorities. 308

It is anticipated that the “modular approach” introduced in this guideline will facilitate management of 309 different frequencies of PBRER submission, and enhance the consistency and quality of the PBRER (see 310 Section 1.1). 311


Independent of the length of the interval covered by the report: 312

• To the extent permitted under national or regional regulatory requirements, regulatory authorities 313 may accept periodic reports based on the IBD of the product, using the content and format 314 described in this guideline. Use of a single harmonised IBD for each product is important in order 315 to reduce the burden of work involved in preparing PBRERs, and respects the original purpose of 316 the PBRER – to prepare a single worldwide summary on a product that can be submitted to 317 regulatory authorities. 318

• For newly approved products, a 6-monthly periodicity applies in many regions, for at least the first 319 2 years after an NME is approved. 320

• For PBRERs submitted on a routine/regular basis, the reports should be based on cumulative data, 321 with interval data sets of 6 months, or multiples thereof. 322

• Whereas sections that provide interval information are likely to need to be updated, the content 323 used in the previous PBRER module can be reviewed and reused for sections where no new 324 information has arisen since preparation of the last PBRER, if appropriate. Specifically, sections 325 that provide evaluation of cumulative data may not need to be updated (see Section 2.7.3.2, 326 Figure 1; Appendix D). 327

2.7.3. PBRERs when periodicity differs across regions 328

When the MAH needs to prepare PBRERs covering different intervals for different regulatory authorities, 329 the following approach should be used, and will eliminate the need for Summary Bridging Reports and 330 Addendum Reports. Summary Bridging Reports and Addendum Reports, introduced in ICH guideline 331 E2C(R1), should no longer be submitted. 332

Each PBRER should be a stand-alone document; the format and table of contents of all reports should 333 be as described in this guideline. Regardless of the duration of the interval covered, each report 334 should include interval data for the period covered, as well as cumulative data. 335

2.7.3.1. PBRERs with data lock points based on the international birth date 336

For two or more PBRERs that have the same data lock point but cover different durations, the 337 cumulative sections of the PBRERs will be the same, whereas the interval sections may differ (see 338 Section 2.7.3.2, Figure 1). 339

The cumulative data sections from the most recent PBRER can be submitted, along with updated 340 interval data in the following sections, as appropriate: 341

• Actions Taken in the Reporting Interval for Safety Reasons (3.3) 342

• Changes to Reference Safety Information (3.4) 343

• Summaries of Significant Safety Findings from Clinical Trials during the Reporting Period (3.7) 344

• Findings from Non-interventional Studies* (3.8) 345

• Information from Other Clinical Trials and Sources (3.9) 346

• Non-clinical data (3.10) 347

• Literature (3.11) 348

• Other Periodic Reports (3.12) 349


• Lack of Efficacy in Controlled Clinical Trials (3.13) 350

• Late-Breaking Information (3.14) 351

For signal evaluation, MAHs should review the relevant sections from individual PBRERs covering the 352 reporting interval, and incorporate the most recent information for each signal newly identified,* 353 ongoing,* or closed* during that reporting interval. 354

For newly identified information on risk and efficacy/effectiveness, the MAH should review the relevant 355 sections from individual PBRERs covering the reporting interval, and incorporate into the PBRER any 356 new information that contributes to the overall benefit-risk evaluation that had not already been 357 included in the CCDS at the beginning of the reporting interval. 358

The cumulative benefit, risk, and integrated benefit-risk evaluation sections of the most recently 359 prepared PBRER should be reviewed and updated, if necessary. 360

2.7.3.2. Ad hoc (“for cause”) PBRERs 361

Ad hoc (“for cause”) PBRERs, i.e., reports outside the specified reporting requirements, are required by 362 some regulatory authorities, generally when there are new risks, when risks have changed, when 363 efficacy/effectiveness has changed, or when there are changes to the benefit-risk profile of a medicinal 364 product (see Section 3.17.1). Ad hoc PBRERs are not typically used to address urgent concerns. For 365 all ad hoc PBRERs, it will be necessary for the regulatory authority to specify the duration of interval 366 data. 367

It is likely that the appropriate data and evaluation sections will need to be updated, and focus on 368 particular concerns raised in the ad hoc request. The overall benefit-risk evaluation and conclusion 369 sections from the most recently submitted PBRER will need to be carefully reviewed and may require 370 revision (Scenario D in Figure 1). 371

Where an ad hoc report is requested and a PBRER has not been prepared for a number of years, it is 372 likely that a completely new report will need to be prepared by the MAH. 373

Where an ad hoc PBRER has been requested by one regulatory authority (e.g., in response to a new 374 safety or benefit-risk concern), the MAH should consider communicating the findings at the same time 375 to the regulatory authorities in other countries where the product is approved. Other regulatory 376 authorities may request copies of the ad hoc PBRER, if desired. 377

378


Figure 1. Submission of PBRERs based on the same data lock point, with various reporting 379 periods. 380

Shading indicates period of interval data. 381

For all reports, the cumulative data reflect all data from the IBD/DIBD. 382

383

384

385

386

387

388

389

390

391

2.7.4. Time interval between data lock point and the submission 392

As a result of the expanded scope of the PBRER, the time interval between the data lock point and 393 submission of PBRERs should be as follows: 394

• PBRERs covering intervals of 6 or 12 months: within 70 calendar days 395

• PBRERs covering intervals in excess of 12 months: within 90 calendar days 396

• Ad hoc PBRERs: 90 calendar days, unless otherwise specified in the ad hoc request. 397

Where national or regional requirements differ from the above, the MAH should discuss the timeline for 398 submission with the relevant regulatory authority. 399

2.8. Format and presentation of PBRER 400

2.8.1. Format 401

The recommended format and content of the PBRER, including table of contents, section numbering, 402 and content of each section, is outlined below. 403

The full ICH guideline E2C(R2) format should be used for all PBRERs. When no relevant information is 404 available or a PBRER section is not applicable, this should be stated. In some countries and regions, 405 the PBRER requirement may be linked to other regulatory documents for pre-approval periodic 406 reporting (i.e., DSUR), post-marketing pharmacovigilance planning and/or risk management. The 407 regulatory authorities and MAHs can take advantage of the modular approach of the PBRER (i.e., 408 sections that can be separated and submitted independently or combined with other documents) to 409 facilitate such regulatory needs, maximize the utility of the content, and reduce duplicate work. 410

2.8.2. Presentation 411

The recommended table of contents, including section numbering, for the PBRER is provided below: 412

IBD DLP

Region A

Region B

Region C

Region D

Region E

time (years)

* update the most recent cumulative and interval data, as appropriate

3

cumulative data are identical

1

6 months

12 months

longer

* ad hoc; PBRERs ongoing in other regions - interval specified in request

ad hoc; PBRER not prepared for other regions

0 2

IBD Data Lock Point


Title Page 413

Executive Summary 414

Table of Contents 415

1. Introduction 416

2. Worldwide Marketing Approval Status 417

3. Actions Taken in the Reporting Interval for Safety Reasons 418

4. Changes to Reference Safety Information 419

5. Estimated Exposure and Use Patterns 420

5.1 Cumulative Subject Exposure in Clinical Trials 421

5.2 Cumulative and Interval Patient Exposure from Marketing Experience 422

6. Data in Summary Tabulations 423

6.1 Reference Information 424

6.2 Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials 425

6.3 Cumulative and Interval Summary Tabulations from Post-marketing Data Sources 426

7. Summaries of Significant Findings from Clinical Trials during the Reporting Period 427

7.1 Completed Clinical Trials 428

7.2 Ongoing Clinical Trials 429

7.3 Long-term Follow-up 430

7.4 Other Therapeutic Use of Medicinal Product 431

7.5 New Safety Data Related to Fixed Combination Therapies 432

8. Findings from Non-interventional Studies 433

9. Information from Other Clinical Trials and Sources 434

10. Non-clinical Data 435

11. Literature 436

12. Other Periodic Reports 437

13. Lack of Efficacy in Controlled Clinical Trials 438

14. Late-Breaking Information 439

15. Overview of Signals: New, Ongoing, or Closed 440

16. Signal and Risk Evaluation 441

16.1 Summary of Safety Concerns 442

16.2 Signal Evaluation 443

16.3 Evaluation of Risks and New Information 444

16.4 Characterisation of Risks 445


16.5 Effectiveness of Risk Minimisation (if applicable) 446

17. Benefit Evaluation 447

17.1 Important Baseline Efficacy/Effectiveness Information 448

17.2 Newly Identified information on Efficacy/Effectiveness 449

17.3 Characterisation of Benefits 450

18. Integrated Benefit-risk Analysis for Approved Indications 451

18.1 Benefit-risk Context - Medical Need and Important Alternatives 452

18.2 Benefit-risk Analysis Evaluation 453

19. Conclusions and Actions 454

20. Appendices 455

3. GUIDANCE ON CONTENTS OF THE PBRER 456

All sections should be completed; when no information is available, this should be stated. Note that 457 section 3.X of this guideline provides information on preparation of Section X of the PBRER, i.e., 458 “Reference Information,” described in Section 3.6.1 of this guideline, refers to Section 6.1 of the 459 PBRER. 460

Title page 461

The title page of the PBRER should include the following information: 462

• date of the report; 463

• medicinal product(s); 464

• International Birth Date; 465

• reporting interval; 466

• MAH(s) name(s) and address(es); and 467

• statement on the confidentiality of the information included in the PBRER. 468

Executive summary 469

This section should provide a concise summary of the most important information contained in the 470 report. 471

The following information should be included in the Executive Summary: 472

• introduction; 473


• medicinal product(s) – mode(s) of action, therapeutic class(es), indication(s), dose(s), route(s) of 475 administration, formulation(s); 476

• estimated cumulative exposure of clinical trial subjects; interval and cumulative post-approval 477 exposure; 478

• number of countries in which the medicinal product is approved; 479


• summary of overall benefit-risk evaluation (based on Section 18.2 of the PBRER); 480

• actions taken or proposed for safety reasons, e.g., significant changes to the labelling, other risk 481 minimisation activities; 482

• conclusions. 483

Table of contents 484

3.1. Introduction 485

Section 1 of the PBRER should include: 486

• international birth date; 487


• medicinal product(s) – mode(s) of action, therapeutic class(es), dose(s), route(s) of 489 administration, formulation(s); 490

• a brief description of the approved indication(s) and population(s) 491

• a brief description and explanation of any information that has not been included in the PBRER; 492 and 493

• the rationale for submission of multiple PBRERs for the medicinal product, if applicable. 494

3.2. Worldwide marketing approval status 495

Section 2 of the PBRER should provide a brief narrative overview including date of first approval, 496 indication(s), approved dose(s), and where approved, if applicable. 497

3.3. Actions taken in the reporting interval for safety reasons 498

Section 3 of the PBRER should include a description of significant actions related to safety that have 499 been taken during the reporting interval, related to either investigational uses or marketing 500 experience, by the MAH, sponsor of a clinical trial(s), regulatory authorities, data monitoring 501 committees, or ethics committees that had: 502

• a significant influence on the benefit-risk profile of the approved medicinal product, and/or 503

• an impact on the conduct of a specific clinical trial(s) or on the overall clinical development 504 programme. 505

The reason(s) for each action should be provided, if known, and additional relevant information should 506 be provided when appropriate. Relevant updates to previous actions should also be summarised in this 507 section. Examples of significant actions taken for safety reasons include: 508

Actions related to investigational drugs:* 509

• refusal to authorise a clinical trial for ethical or safety reasons; 510

• partial5 or complete clinical trial suspension or early termination of an ongoing clinical trial* 511 because of safety findings or lack of efficacy; 512

5 “Partial suspension” might include several actions (e.g., suspension of repeat dose studies, but continuation of single dose studies; suspension of trials in one indication, but continuation in another, and/or suspension of a particular dosing regimen in a trial but continuation of other doses).


• recall of investigational drug or comparator; 513

• failure to obtain marketing approval for a tested indication, including voluntary withdrawal of a 514 marketing application; 515

• risk management activities, including: 516

− protocol modifications due to safety or efficacy concerns (e.g., dosage changes, changes in 517 study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial 518 duration); 519

− restrictions in study population or indications; 520

− changes to the informed consent document relating to safety concerns; 521

− formulation changes; 522

− addition by regulators of a special safety-related reporting requirement; 523

− issuance of a communication to investigators or healthcare professionals; and 524

− plans for new studies to address safety concerns. 525

Actions related to marketed drugs: 526

• failure to obtain a marketing approval renewal; 527

• withdrawal or suspension of a marketing approval; 528

• risk management activities including: 529

− Significant restrictions on distribution or introduction of other risk minimisation measures; 530

− significant safety-related changes in labelling documents that could affect the development 531 programme, including restrictions on use or population treated; 532

− communications to health care professionals; and 533

− new post-marketing study requirement(s) imposed by regulators. 534

3.4. Changes to reference safety information 535

Section 4 of the PBRER should list any significant changes to the reference safety information within 536 the reporting interval. Such changes might include information relating to contraindications, warnings, 537 precautions, serious adverse drug reactions (ADRs), adverse events of special interest, and 538 interactions; important findings from ongoing and completed clinical trials;* and significant non-clinical 539 findings (e.g., carcinogenicity studies). Specific information relevant to these changes should be 540 provided in the appropriate sections of the PBRER. A tracked changes version of the reference 541 document should be included (as an attachment) that identifies changes over the reporting interval. 542

The MAH should also provide, in a regional appendix, information on any final, ongoing, or proposed 543 changes to the national or local authorised product information based on the most recent version of 544 the CCSI. 545

3.5. Estimated exposure and use patterns 546

Sections 5.1 and 5.2 of the PBRER should provide estimates of the size and nature of the population 547 exposed to the medicinal product. Section 5.1 of the PBRER should provide information on cumulative 548 exposure in clinical trials. Section 5.2 should provide cumulative and interval exposure in the 549


marketed setting. Brief descriptions of the method(s) used to estimate the subject/patient exposure 550 should be described, as well as the limitations thereof. Consistent methods for calculating patient 551 exposure should be used across PBRERs for the same product. If a change in the method is 552 appropriate, both methods and calculations should be provided in the PBRER introducing the change. 553

3.5.1. Cumulative subject exposure in clinical trials 554

Section 5.1 of the PBRER should include the following information, if applicable, presented in tabular 555 format (see Appendix B, Tables 1-3 for examples): 556

• Cumulative numbers of subjects from ongoing and completed clinical trials exposed to the 557 investigational medicinal product, placebo, and/or active comparator(s) since the DIBD. It is 558 recognised that for older products, detailed data might not be available. 559

• More detailed cumulative subject exposure in clinical trials should be presented if available, e.g., 560 sub-grouped by age, sex, and racial group for the entire development programme. 561

• Important differences among trials in dose, routes of administration, or patient populations can be 562 noted in the tables, if applicable, or separate tables can be considered. 563

• If clinical trials have been or are being performed in special populations (e.g., pregnant women; 564 patients with renal, hepatic, or cardiac impairment; or patients with relevant genetic 565 polymorphisms), exposure data should be provided, as appropriate. 566

• When there are substantial differences in time of exposure between subjects randomised to the 567 investigational medicinal product or comparator(s), or disparities in length of exposure between 568 clinical trials, it can be useful to express exposure in subject-time (subject-days, -months, or -569 years). 570

• Investigational drug exposure in healthy volunteers might be less relevant to the overall safety 571 profile, depending on the type of adverse reaction, particularly when subjects are exposed to a 572 single dose. Such data can be presented separately with an explanation as appropriate. 573

• If the serious adverse events (SAEs) from clinical trials are presented by indication in the summary 574 tabulations, the patient exposure should also be presented by indication, where available. 575

• For individual trials of particular importance, demographic characteristics should be provided 576 separately. 577

3.5.2. Cumulative and interval patient exposure from marketing experience 578

When possible, separate estimations should be provided for cumulative exposure (since the IBD) and 579 interval exposure (since the data lock point of the previous PBRER), see Appendix B, Tables 4-5 for 580 examples. Although the difficulty of obtaining and validating exposure data is recognised, the 581 estimated number of patients exposed should be provided when possible, along with the method(s) 582 used to determine the estimate. A justification should be provided if an estimate of the number of 583 patients exposed is impossible to obtain. If an estimate of the number of patients is not available, 584 alternative estimated measures of exposure, if available, should be presented along with the 585 method(s) used to derive them. Examples of alternative measures of exposure include patient-days of 586 exposure and number of prescriptions. Only if such measures are not available, measures of drug 587 sales, such as tonnage or dosage units, may be used. The concept of a defined daily dose may also be 588 used to arrive at patient exposure estimates. 589

The data should be presented according to the following categories: 590


1. Post-approval (non-clinical trial) exposure: 591

An overall estimation of patient exposure should be provided. 592

In addition, the data should be routinely presented by indication, sex, age, dose, formulation, and 593 region, where applicable. 594

Depending upon the product, other variables may be relevant, such as number of vaccination courses, 595 route(s) of administration, and duration of treatment. 596

When there are patterns of reports indicating a safety signal, exposure data within relevant subgroups 597 should be presented, if possible. 598

2. Post-approval use in special populations 599

Where post-approval use has occurred in special populations, available information regarding 600 cumulative patient numbers exposed and the method of calculation should be provided. Sources of 601 such data would include non-interventional studies designed to obtain this information, including 602 registries. Populations to be considered for discussion include, but might not be limited to: 603

• paediatric population; 604

• elderly population; 605

• pregnant or lactating women; 606

• patients with hepatic and/or renal impairment; 607

• patients with other relevant co-morbidity; 608

• patients with disease severity different from that studied in clinical trials; 609

• sub-populations carrying relevant genetic polymorphism(s); 610

• patients of different racial and/or ethnic origins. 611

3. Patterns of Use of the Medicinal Product 612

If the MAH becomes aware of patterns of use of the medicinal product considered relevant for the 613 interpretation of safety data, provide a brief description thereof. Such patterns may include, in 614 particular, off-label use (e.g., an anti-epileptic drug used off-label for neuropathic pain and/or 615 prophylaxis of migraine headaches). If known, the MAH may briefly comment on whether such off-616 label use is supported by clinical guidelines, clinical trial evidence, or an absence of approved 617 alternative treatments. Quantitative use information should be provided, if available. For purposes of 618 identifying which patterns of use are off-label, the MAH should reference the CCDS in the PBRER. 619

3.6. Data in summary tabulations 620

Sections 6.1-6.3 of the PBRER should present cumulative summary tabulations of SAEs from clinical 621 trials and post-marketing sources that have been reported to the MAH since the DIBD. At the 622 discretion of the MAH, graphical displays can be used to illustrate specific aspects of the data when 623 useful to enhance understanding. 624

3.6.1. Reference information 625

Section 6.1 of the PBRER should specify the version(s) of the coding dictionary used for analyses of 626 adverse reactions. 627


3.6.2. Cumulative summary tabulations of serious adverse events from 628 clinical trials 629

Section 6.2 of the PBRER should provide background for the appendix that provides a cumulative 630 summary tabulation of SAEs reported in the MAH’s clinical trials, from the DIBD to the data lock point 631 of the current PBRER. The MAH should explain any omission of data (e.g., clinical trial data might not 632 be available for products marketed for many years). The tabulation(s) should be organised by system 633 organ class (SOC), for the investigational drug, as well as for the comparator arm(s) (active 634 comparators, placebo) used in the clinical development programme. Data can be integrated across the 635 programme. Alternatively, when useful and feasible, tabulations of SAEs can be presented by trial, 636 indication, route of administration, or other variables. This section should not serve to provide 637 analyses or conclusions based on the SAEs. 638

Appendix B, Table 6 of this guideline provides an example of summary tabulations of serious adverse 639 events from clinical trials. The following points should be considered: 640

• In general, the tabulation(s) of SAEs from clinical trials should include only those terms that were 641 used in defining the case as serious; they should not include non-serious events. 642

• When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the 643 adverse event/reaction terms, the Preferred Term level and SOC should be presented in the 644 summary tabulations. 645

• The tabulations should include blinded and unblinded clinical trial data. Unblinded serious adverse 646 events might originate from completed trials and individual cases that have been unblinded for 647 safety-related reasons (e.g., expedited reporting), if applicable. Sponsors/MAHs should not 648 unblind data for the specific purpose of preparing the PBRER. 649

• Certain adverse events in clinical trials can be excluded from the clinical trials summary 650 tabulations, but such exclusions should be explained in the report. For example, adverse events 651 that have been defined in the protocol as “exempt” from special collection and entry into the safety 652 database because they are anticipated in the patient population, and those that represent study 653 endpoints, can be excluded (e.g., deaths reported in a trial of a drug for congestive heart failure 654 where all-cause mortality is the primary efficacy endpoint, disease progression in cancer trials). 655

• Causality assessment is generally useful for the evaluation of individual rare ADRs. Individual case 656 causality assessment has less value in the analysis of aggregate data, where group comparisons of 657 rates are possible. Therefore, the summary tabulations should include all SAEs for the 658 investigational drug, active controls, and placebo. It may be useful to give rates by dose. 659

3.6.3. Cumulative and interval summary tabulations from post-marketing 660 data sources 661

Section 6.3 of the PBRER should provide background for the appendix that provides cumulative and 662 interval summary tabulations of adverse reactions, from the IBD to the data lock point of the current 663 PBRER. These adverse reactions are derived from non-interventional studies and spontaneous ICSRs, 664 including reports from healthcare professionals, consumers, scientific literature, regulatory authorities. 665 Serious and non-serious reactions should be presented in a single table, with interval and cumulative 666 data presented side-by-side (see Appendix B, Table 7). The table should be organised by SOC. For 667 special issues or concerns, additional tabulations of adverse reactions can be presented by indication, 668 route of administration, or other variables. This section should not serve to provide analyses or 669 conclusions based on the data presented. As described in ICH guideline E2D, for marketed medicinal 670


products, spontaneously reported* adverse events usually imply at least a suspicion of causality by the 671 reporter, and should be considered to be adverse reactions for regulatory reporting purposes. 672

3.7. Summaries of significant safety findings from clinical trials during the 673 reporting period 674

A listing of any MAH-sponsored interventional trials with the primary aim of identifying, characterising, 675 or quantifying a safety hazard, confirming the safety profile of the medicinal product, or measuring the 676 effectiveness of risk management measures that were completed or ongoing during the reporting 677 interval (i.e., post-authorisation safety studies, PASS*), should be included in an appendix. 678

When possible and relevant, data categorized by sex and age (particularly children versus adult), 679 indication, dose, and region should be presented. 680

The signals arising from clinical trial sources should be tabulated in Section 15 of the PBRER. For those 681 that are considered to be either a potential* or identified risk,* the risk should be evaluated and 682 characterised in Sections 16.3 and 16.4, respectively. 683

3.7.1. Completed clinical trials 684

Section 7.1 of the PBRER should provide a brief summary of clinically important emerging efficacy and 685 safety findings obtained from clinical trials completed during the reporting interval. This information 686 can be presented in narrative format or as a synopsis. It could include information that supports or 687 refutes previously identified safety concerns, as well as evidence of new safety signals. 688

3.7.2. Ongoing clinical trials 689

If the MAH is aware of clinically important information that has arisen from ongoing clinical trials (e.g., 690 learned through interim safety analyses or as a result of unblinding of subjects with adverse events), 691 this section should briefly summarise the concern(s). It could include information that supports or 692 refutes previously identified safety concerns, as well as evidence of new safety signals. 693

3.7.3. Long-term follow-up 694

Where applicable, this section should provide information from long-term follow-up of subjects from 695 clinical trials of investigational drugs, particularly advanced therapy products. 696

3.7.4. Other therapeutic use of medicinal product 697

This section of the PBRER should include clinically important safety information from other programmes 698 conducted by the MAH that follow a specific protocol, with solicited reporting as per ICH guideline E2D 699 (e.g., expanded access programmes, compassionate use programmes, particular patient use, single-700 patient investigational new drug applications (INDs), treatment INDs, and other organised data 701 collection). 702

3.7.5. New safety data related to fixed combination therapies 703

Unless otherwise specified by national or regional regulatory requirements, the following options can 704 be used to present data from combination therapies. 705


• If the product that is the subject of a PBRER is also approved or under development as a 706 component of a fixed combination product or a multi-drug regimen, this section should summarise 707 important safety findings from use of the combination therapy. 708

• If this PBRER is for a fixed combination product, this section should summarise important safety 709 information arising from the individual components whether approved or under development. 710

The information specific to the combination can be incorporated into a separate section(s) of the 711 PBRER for one or all of the individual components of the combination. 712

3.8. Findings from non-interventional studies 713

This section should summarise relevant safety information or information with potential impact on the 714 benefit or risk evaluations, from MAH-sponsored non-interventional studies that became available 715 during the reporting interval (e.g., observational studies, epidemiological studies, registries, and active 716 surveillance programmes). This should include relevant information from drug utilisation studies when 717 applicable to multiple regions. 718

A listing of any MAH-sponsored non-interventional study(s) with the primary aim of identifying, 719 characterising, or quantifying a safety hazard, confirming the safety profile of the medicinal product, or 720 measuring the effectiveness of risk management measures that were completed or ongoing during the 721 reporting interval (i.e., post-authorisation safety studies), should be included in an appendix. Progress 722 or final study reports generated during the reporting period for post-authorisation safety studies 723 (PASS) should also be included as a regional appendix to the report. 724

3.9. Information from other clinical trials and sources 725

This section should summarise information relevant to the risk evaluation of the medicinal product 726 from any other clinical trial/study sources that is accessible by the MAH with reasonable and 727 appropriate effort, and became available to the MAH during the reporting interval (e.g., results from 728 pooled analyses or meta-analyses of randomised clinical trials, safety information provided by co-729 development partners or from investigator-initiated trials). 730

3.10. Non-clinical data 731

This section should summarise major safety findings from non-clinical in vivo and in vitro studies (e.g., 732 carcinogenicity, reproduction, or immunotoxicity studies) ongoing or completed during the reporting 733 interval. Implications of these findings should be discussed in Sections 16 and 18 of the PBRER. 734

3.11. Literature 735

This section should summarise new and significant safety findings, either published in the peer-736 reviewed scientific literature or made available as unpublished manuscripts, relevant to the approved 737 medicinal product that the MAH became aware of during the reporting interval. Literature searches for 738 PBRERs should be wider than those for individual adverse reaction cases as they should also include 739 studies reporting safety outcomes in groups of subjects. If relevant and applicable, information on 740 active substances of the same class should be considered. 741

3.12. Other periodic reports 742

Unless otherwise specified by national or regional regulatory requirements, the MAH should prepare a 743 single PBRER for a single active substance. However, if an MAH prepares multiple PBRERs for a single 744


medicinal product (e.g., covering different indications, or formulations), this section should summarise 745 significant findings from the other periodic reports if they are not presented elsewhere within this 746 report. 747

When available, based on contractual agreements, the MAH should summarise significant findings from 748 periodic reports provided during the reporting interval by other parties (e.g., sponsors, MAHs, other 749 contractual partners). 750

3.13. Lack of efficacy in controlled clinical trials 751

Data from clinical trials indicating lack of efficacy, or lack of efficacy relative to established 752 therapy(ies), for products intended to treat or prevent serious or life-threatening illnesses (e.g., excess 753 cardiovascular adverse events in a trial of a new anti-platelet drug for acute coronary syndromes) 754 could reflect a significant risk to the treated population and should be summarised in this section. 755 When relevant to the benefit-risk evaluation, clinical trials demonstrating lack of efficacy for products 756 not intended for treatment of life-threatening diseases in the approved indications should also be 757 summarised. 758

3.14. Late-breaking information 759

This section should summarise information on potentially important safety and efficacy/effectiveness 760 findings that arise after the data lock point, but while the PBRER is in preparation. Examples include 761 clinically significant new publications, important follow-up data, clinically relevant toxicological findings 762 and any action that the MAH, a data monitoring committee, or a regulatory authority has taken for 763 safety reasons. New individual case reports should not be included unless they are considered to 764 constitute an important index case (i.e., the first instance of an important event) or an important 765 safety signal. 766

The Evaluation of Risks and New Information (see Section 3.16.3 of this guideline) should also take 767 these new data into account. 768

3.15. Overview of signals: new, ongoing or closed 769

The purpose of this section is to provide an overview of signals detected, under review, and evaluated 770 during the reporting interval. 771

A brief description of the method of signal detection* used, as well as the sources screened for signals, 772 should be provided. 773

A newly identified signal refers to a signal that has been identified during the reporting interval. An 774 ongoing signal refers to a signal that was still under evaluation at the data lock point. A closed signal 775 refers to a signal for which an evaluation was completed during the reporting interval. Signals that are 776 both newly identified and closed during the reporting interval should be handled in this section as 777 closed signals (i.e., signals detected during the reporting period, with evaluation completed within the 778 reporting period). 779

This section should reference a tabulation of signals that are new, ongoing, and closed during the 780 reporting interval. The tabulation should be provided as an appendix to the PBRER and conform to the 781 template annexed to this guideline (see Appendix C). At the discretion of the MAH, this tabulation may 782 also provide cumulative signal data by including previously closed signals, in which case the MAH 783 should specify the starting point (date) for the cumulative data. 784


Detailed signal evaluations will not be included in this section but will instead be presented in Sections 785 16.2 (Signal Evaluation) and 16.3 (Evaluation of Risks and New Information) of the PBRER. 786

3.16. Signal and risk evaluation 787

3.16.1. Summary of safety concerns 788

The purpose of this section is to provide a summary of important safety concerns at baseline, i.e., at 789 the beginning of the reporting interval, against which new information and evaluations can be made. 790 The following factors should be considered when determining the importance of each risk: 791

• medical seriousness of the risk, including the impact on individual patient; 792

• its frequency, predictability, preventability, and reversibility; 793

• potential impact on public health (frequency; size of treated population); and 794

• public perception of risk where it may impact public heath, e.g., avoidance of vaccines. 795

The summary should present the following safety information, as of the beginning of the reporting 796 interval of the current PBRER: 797

• important identified risks;* 798

• important potential risks;* and 799

• important missing information.* 800

For products with an existing safety specification, this will be the same as the safety specification 801 summary of ICH guideline E2E at the start of the reporting interval. 802

For products without an existing safety specification, this section should provide information on the 803 important identified and potential risks associated with use of the product, based on pre- and post-804 approval experience. These may include, for example: 805

• important adverse reactions; 806

• interactions with other medicinal products; 807

• interactions with foods and other substances; 808

• medication errors; 809

• effects of occupational exposure; and 810

• pharmacological class effects. 811

The summary on important missing information should take into account whether there are critical 812 gaps in knowledge for specific safety issues or populations that use the medicinal product. 813

3.16.2. Signal evaluation 814

Section 16.2 of the PBRER should summarize the results of evaluations of safety signals that were 815 closed during the reporting interval. There will be two main categories: 816

1. Those signals that, following evaluation, have been categorised as a potential or identified risk, 817 including lack of efficacy. These closed signals should be discussed in PBRER Section 16.3, Evaluation 818 of Risks and New Information. 819


2. Those signals that, following evaluation, have been rejected as false signals based on a 820 scientific evaluation of the currently available information. For this category of signals, a description of 821 each signal evaluation should be included in order to provide the basis upon which the signal was 822 rejected. This description can be included in this section of the PBRER, or in an appendix. 823

For signals that have had a completed evaluation during the interval, it is recommended that the level 824 of detail provided in the description of the signal evaluation be proportionate to the public health 825 importance of the concern and the extent of the available evidence, and should include the following 826 information as appropriate: 827

• source or trigger of the signal; 828

• background relevant to the evaluation; 829

• methods of evaluation, including data sources, search criteria, and analytical approaches; 830

• results – a summary and critical analysis of the data considered in the signal evaluation; 831

• discussion; and 832

• conclusion, including proposed actions. 833

3.16.3. Evaluation of risks and new information 834

This section should provide a critical appraisal of all new information on all risks, which can be 835 categorised as “important” or “other.” This includes newly detected potential and identified risks, as 836 well as new information relevant to previously identified risks. This section should not summarise or 837 repeat information presented in previous sections of the PBRER, but should provide an interpretation of 838 the new information, with a view towards characterising the risk profile. 839

New information can be organised as follows: 840

1. new potential risks 841

2. new identified risks 842

3. new information on previously detected risks (potential or identified) 843

4. update on important missing information 844

Concise summaries of the evaluations of important risks should be provided. For “other” risks not 845 classified as “important,” for which new information has emerged during the reporting interval, the 846 level of detail should be proportional to the available evidence on the risk and its public health 847 relevance. 848

Any new information on populations exposed or data generated to address previously missing 849 information should be critically assessed in this section. Unresolved concerns and uncertainties should 850 be acknowledged. 851

3.16.4. Characterisation of risks 852

This section will characterise important identified and potential risks based on cumulative data (i.e., 853 not restricted to the reporting interval), and describe important missing information. 854

Depending on the nature of the data source, the characterisation of risk may include, where applicable: 855

• frequency; 856


• numbers of cases (numerator); precision of estimate, taking into account the source of the data; 857

• extent of use (denominator) expressed as numbers of patients, patient-time, etc., and precision of 858 estimate; 859

• estimate of relative risk; precision of estimate; 860

• estimate of absolute risk; precision of estimate; 861

• impact on the individual patient (effects on symptoms, quality or quantity of life); 862

• public health impact; 863

• risk factors (e.g., patient factors [age, pregnancy/lactation, hepatic/renal impairment, relevant co-864 morbidity, disease severity, genetic polymorphism, racial and/or ethnic origin], dose); 865

• duration of treatment, risk period; 866

• preventability (i.e., predictability, ability to monitor for a “sentinel” adverse reaction or laboratory 867 marker); 868

• reversibility; 869

• potential mechanism; and 870

• strength of evidence and its uncertainties, including analysis of conflicting evidence, if applicable. 871

For PBRERs for products with several indications, formulations, or routes of administration, where 872 there may be significant differences in the identified and potential risks, it may be appropriate to 873 present risks by indication, formulation, or route of administration. Headings that could be considered 874 include: 875

• risks relating to the active substance; 876

• risks related to a specific formulation or route of administration (including occupational exposure); 877

• risks relating to a specific population; 878

• risks associated with non-prescription use (for compounds that are available as both prescription 879 and non-prescription products); and 880

• safety concerns regarding missing information. 881

3.16.5. Effectiveness of risk minimisation (if applicable) 882

Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for 883 important identified risks that has become available during the reporting interval should be 884 summarised in this section. 885

Insights into the effectiveness of risk minimisation activities that may be applicable across multiple 886 regions are of particular interest. Information may be summarised by region, if applicable and 887 relevant. 888

Results of evaluations that became available during the reporting interval should be provided in 889 regional appendices to comply with national or regional requirements. 890


3.17. Benefit evaluation 891

3.17.1. Important baseline efficacy/effectiveness information 892

This section summarises information on the efficacy/effectiveness of the medicinal product at baseline, 893 i.e., as of the beginning of the reporting interval. This information should relate to the approved 894 indication(s) of the medicinal product, listed in the CCDS. 895

For medicinal products with multiple indications, populations, and/or routes of administration, the 896 benefit should be characterised separately by these factors. 897

When there have been no significant changes in the benefit or risk profile of the medicinal product in 898 the reporting interval, the summary should be succinct, essentially the content of the CCDS. 899

For medicinal products where there have been significant changes in either the risk or benefit profile, 900 the section should include sufficient information to support an updated characterisation of the benefit 901 of the medicinal product in section 17.3 of the PBRER. The type and extent of the information 902 presented will vary by product, and may include the following, if available and relevant: 903

• a brief description of the epidemiology and natural history of the disease; 904

• nature of the benefit: e.g., diagnostic, preventive, symptomatic, or disease-modifying treatment; 905

• important endpoints that support the benefit, e.g., effects on mortality, symptoms, patient 906 reported outcomes; 907

• evidence of efficacy/effectiveness of comparators, e.g., active-controlled trials, meta-analyses, 908 observational studies, if applicable; and 909

• when relevant to the benefit-risk evaluation, trends, patterns and/or evidence of benefit in 910 important subgroups, e.g., age, sex, ethnicity, disease severity, or genetic polymorphism. 911

3.17.2. Newly identified information on efficacy/effectiveness 912

Additional information on efficacy/effectiveness in approved indications that may have become 913 available during the reporting interval should be presented in this section. For approved indications, 914 new information on efficacy/effectiveness under conditions of actual use should also be described in 915 this section, if available. New information about efficacy/effectiveness in uses other than the approved 916 indication(s) should not be included, unless relevant for the benefit-risk evaluation in the approved 917 indication. 918

Particular attention should be given to changes in the therapeutic environment that could impact 919 efficacy/effectiveness over time, e.g., vaccines, emergence of resistance to anti-infective agents, 920 availability of new medicinal products. 921

The type and extent of the information presented will vary by product, and could refer to PBRER 922 section 17.1 if no new information became available. 923

3.17.3. Characterisation of benefits 924

Section 17.3 of the PBRER provides an integration of the baseline benefit information and any relevant 925 new benefit information that became available during the reporting interval for approved indications. 926

When there are no new relevant benefit data, and no significant change in risk profile, this section 927 should refer to PBRER Section 17.1. 928


When there is new positive benefit information and no significant change in the risk profile in this 929 reporting interval, the integration of baseline and new information in this section should be succinct. 930

When there is significant change to the risk profile, or new evidence that suggests benefit is 931 significantly less than originally demonstrated, this section should provide a concise but critical 932 evaluation of the strengths and limitations of the evidence on efficacy/effectiveness, considering the 933 following, when available: 934

• a brief description of the strength of evidence of benefit, considering comparator(s), effect size, 935 statistical rigor, methodological strengths and deficiencies, and consistency of findings across 936 trials/studies; 937

• new information that challenges the validity of a surrogate endpoint, if used; 938

• clinical relevance of the effect size; 939

• generalizability of treatment response across the indicated patient population, e.g., information 940 that demonstrates lack of treatment effect in a sub-population; 941

• adequacy of characterization of dose-response; 942

• duration of effect; 943

• comparative efficacy; and 944

• a determination of the extent to which efficacy findings from clinical trials are generalizable to 945 patient populations treated in medical practice. 946

3.18. Integrated benefit-risk analysis for approved Indications 947

The purpose of this section is to provide an overall appraisal of the benefit and risk of the medicinal 948 product as used in clinical practice. This section should provide a critical analysis and integration of 949 the information in the previous sections with respect to benefit and risk, and should not duplicate the 950 benefit and risk information presented in Sections 16.3 and 17.3. 951

3.18.1. Benefit-risk context - medical need and important alternatives 952

This section should provide a brief description of the medical need for the medicinal product in the 953 approved indications, and summarise alternatives (medical, surgical, or other; including no treatment). 954

3.18.2. Benefit-risk analysis evaluation 955

A benefit-risk profile is specific to an indication and population. For products approved for more than 956 one indication, benefit-risk profiles should be evaluated and presented for each indication individually. 957 If there are important differences in the benefit-risk profiles among populations within an indication, 958 benefit-risk evaluation should be presented by population, if possible. The benefit-risk evaluation 959 should be presented in a structured manner as described below. 960

General points regarding benefit and risk: 961

• Whereas previous sections will include all important benefit and risk information, not all benefits 962 and risks contribute importantly to the overall benefit-risk evaluation. Therefore, the key benefits 963 and risks considered in the evaluation should be specified. The key information presented in the 964 previous benefit and risk sections should be carried forward for integration in the benefit-risk 965 evaluation. 966


• Consider the context of use of the medicinal product: the condition to be treated, prevented, or 967 diagnosed; its severity and seriousness; and the population to be treated (relatively healthy; 968 chronic illness). 969

• With respect to benefit, consider its nature, clinical importance, duration, and generalizability, as 970 well as evidence of efficacy in non-responders to other therapies and alternative treatments. 971 Consider the effect size. If there are individual elements of benefit, consider all (e.g., for therapies 972 for arthritis: reduction of symptoms and inhibition of radiographic progression of joint damage). 973

• With respect to risk, consider its clinical importance, e.g., nature of toxicity, seriousness, frequency, 974 predictability, preventability, reversibility, impact on patients, and whether it arose from off-label 975 use, a new use, or misuse. 976

• The strengths, weaknesses, and uncertainties of the evidence should be considered when 977 formulating the benefit-risk evaluation. Describe how uncertainties in the benefits and risks impact 978 the evaluation. For example, uncertainty in important benefits and/or risks may reduce their 979 contribution(s) to the evaluation. Limitations of the assessment should be discussed. 980

Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk 981 evaluation: 982

• The assumptions, considerations, and judgement or weighting that support the conclusions of the 983 benefit-risk evaluation should be clear. 984

• Comment on the feasibility of expressing benefits and risks in such a way as to facilitate their 985 comparison. 986

• If a formal quantitative assessment of benefit-risk is provided, a summary of the methods should 987 be included. 988

• Economic considerations (e.g., cost-effectiveness) should not be considered in the benefit-risk 989 evaluation. 990

When there is important new information or an ad hoc PBRER has been requested, a detailed benefit-991 risk analysis based on cumulative data would be appropriate. Conversely, where little new information 992 has become available during the reporting interval, the primary focus of the benefit-risk evaluation 993 might consist of an evaluation of updated interval safety data, with the understanding that the overall 994 benefit-risk profile has not changed during the reporting interval. 995

3.19. Conclusions and actions 996

This section should provide a conclusion about the implications of any new information that arose 997 during the reporting interval, in terms of the overall benefit-risk evaluation, for each approved 998 indication, as well as for relevant subgroups, if appropriate. 999

Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the MAH should 1000 assess the need for changes to the CCDS and propose changes as appropriate. 1001

In addition, the conclusion should include preliminary proposal(s) to optimise or further evaluate the 1002 benefit-risk balance, for further discussion with the relevant regulatory authorities. This may include 1003 proposals for additional risk minimisation activities. 1004

For products with an E2E (Pharmacovigilance Planning) document, the proposals should be 1005 incorporated into the E2E pharmacovigilance plan and risk minimisation plan. 1006


3.20. Appendices to the PBRER 1007

The PBRER should be accompanied by the following appendices, as appropriate, numbered as follows: 1008

1 Reference Information; 1009

2 Cumulative Summary Tabulation of Serious Adverse Events from Clinical trials and 1010 Interval/Cumulative Summary Tabulations from Marketed Experience; 1011

3 Tabular Summary of Safety Signals; 1012

4 Listing of all Post-authorisation Safety Studies (PASS); 1013

5 List of the Sources of Information Used to Prepare the PBRER (when desired by the MAH). 1014

The PBRER may also be accompanied by regional appendices, as needed, to fulfil national and regional 1015 requirements. 1016

4. APPENDICES TO THIS GUIDELINE 1017

Appendix A Glossary 1018

Appendix B Examples of Summary Tabulations 1019

Appendix C Tabular Summary of Safety Signals that were New, Ongoing, or Closed during the 1020 Reporting Interval 1021

Appendix D List of PBRER Sections, Identified as Providing Cumulative or Interval Information, and 1022 Ability to Share Modules with Other Regulatory Documents 1023

Appendix E Examples of Possible Sources of Information That May Be Used in the Preparation of the 1024 PBRER6 1025

6 Examples of potential sources of information to be used in preparation of a PBRER will be included in the Step 4 guideline as general guidance. Suggestions for information sources to be included in this list should be submitted during the consultation period.


APPENDIX A – Glossary 1026

Whenever possible the Working Group has used terms in use in other ICH guidelines, or those previously proposed by Council for International 1027 Organizations of Medical Sciences (CIOMS) working groups. Generally, the definitions of terms previously defined in ICH documents are not repeated in 1028 this glossary, except for those of particular importance to the PBRER. 1029

Item Glossary Term Source of Definition Definition/Commentary

1. Closed signal ICH guideline E2C (R2) A signal for which an evaluation was completed during the reporting interval.

2. Company Core Data Sheet (CCDS)

ICH guideline E2C A document prepared by the MAH containing, in addition to safety information, material related to indications, dosing, pharmacology and other information concerning the product.

3. Company Core Safety Information (CCSI)

ICH guideline E2C All relevant safety information contained in the CCDS prepared by the MAH and which the MAH requires to be listed in all countries where the company markets the drug, except when the local regulatory authority specifically requires a modification. It is the reference information by which listed and unlisted are determined for the purposes of periodic reporting for marketed products, but not by which expected ad unexpected are determined for expedited reporting.

4. Completed clinical trial ICH guideline E2F Study for which a final clinical study report is available. 5. Identified risk ICH guideline E2F

An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest. Examples of identified risks include: an adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data; an adverse reaction observed in well designed clinical trials or epidemiological studies for which the magnitude of the difference compared with the comparator group (placebo or active substance) on a parameter of interest suggests a causal relationship;



an adverse reaction suggested by a number of well documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions.

6. Important identified risk, important potential risk

ICH guideline E2C(R2) An identified risk or potential risk that could impact on the risk-benefit profile of the product or have implications for public health. What constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk, and the impact on public health. Normally, any risk that is likely to be included in the contraindications or warnings and precautions section of the product labelling should be considered important.

7. Important missing information

ICH guideline E2C(R2) Critical gaps in knowledge for specific safety issues or populations that use the marketed product.

8. Investigational drug ICH guideline E2F The term investigational drug is used in this guideline to indicate only the experimental product under study or development. Note: This term is more specific than “investigational medicinal product”, which includes comparators and placebos.

9. Module/modular approach

ICH guideline E2C(R2) Sections of a report that have been written to facilitate their use in more than one regulatory document.

10. Newly identified signal ICH guideline E2C(R2) A signal first identified during the reporting interval, prompting further actions for evaluation.

11. Non-interventional clinical study

ICH guideline E2F A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing approval. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.



12. Ongoing clinical trial ICH guideline E2F Trial where enrolment has begun, whether a hold is in place or analysis is complete, but for which a final clinical study report is not available.

13. Ongoing signal ICH guideline E2C (R2) A signal that had been identified before the reporting interval, that was still under evaluation at the data lock point.

14. Post-Authorisation Safety Study (PASS)

Revised 2001/83/EC amendment (Article 1[c] 15)

Any study relating to an approved medicinal product conducted with the aim of identifying, characterising, or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures.

15. Potential risk ICH guideline E2F

An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed. Examples of potential risks include: non-clinical safety concerns that have not been observed or resolved in clinical studies; adverse events observed in clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group (placebo or active substance, or unexposed group), on the parameter of interest raises a suspicion of, but is not large enough to suggest, a causal relationship; a signal arising from a spontaneous adverse reaction reporting system; an event which is known to be associated with other products of the same class or which could be expected to occur based on the properties of the medicinal product.

16. Reference Safety Information

ICH guideline E2C(R2) Referred to as the CCSI, a subset of information contained within the MAH’s central document (CCDS).

17. Risk minimisation activities

ICH guideline E2C(R2) Public health interventions intended to prevent or reduce the probability of the occurrence of ADRs associated with the exposure to



a medicine, or to reduce their severity should they occur. The aim of a risk minimisation activity is to reduce the probability or severity of an adverse reaction. These activities may consist of routine risk minimisation (e.g., product labelling) or additional risk minimisation activities (e.g., professional or patient communications/educational materials).

18. Safety concern ICH guideline E2C(R2) An important identified risk, important potential risk, or important missing information.

19. Signal ICH guideline E2C(R2) Information that arises from one or multiple sources (including observations and experiments), that suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify further action to verify.

20. Signal detection ICH guideline E2C(R2) The act of looking for and/or identifying signals using data from any source. It should be noted that a safety signal is not synonymous with a statistic of disproportionate reporting, a numerical result above a preset threshold generated from any data mining algorithm using disproportionality analysis applied to a spontaneous report database.

21. Spontaneous Report or Spontaneous Notification

ICH guideline E2D An unsolicited communication to a company, regulatory authority, or other organization that describes an ADR in a patient given one or more medicinal products and which does not derive from a study or any organized data collection scheme.


APPENDIX B – Examples of summary tabulations 1030

Table 1 – Estimated Cumulative Subject Exposure from Clinical Trials 1031

Estimates of cumulative subject exposure, based upon actual exposure data from completed clinical 1032 trials and the enrolment/randomisation schemes for ongoing trials. 1033

Treatment Number of subjects

medicinal product

Comparator

Placebo

Table 2 – Cumulative Subject Exposure to Investigational Drug from Completed Clinical 1034 Trials by Age and Sex* 1035

Number of subjects

Age range Male Female Total

* Data from completed trials as of [date] 1036

Table 3 – Cumulative Subject Exposure to Investigational Drug from Completed Clinical 1037 Trials by Racial Group* 1038

Racial group Number of subjects

Asian

Black

Caucasian

Other

Unknown

Total

* Data from completed studies as of [date] 1039

1040


Table 4 – Cumulative exposure from marketing experience 1041

Table 4 includes cumulative data obtained from month/day/year through month/day/year, where 1042 available. 1043

Table 5 – Interval Exposure from Marketing Experience 1044

indication sex age (years) dose (mg/day)

formulation region

male female 2 to ≤16

>16 to 65

>65 unknown

<40 ≥40 unknown

IV oral EU

Japan

Mexico

US/Canada

other

depression

migraine

Table 5 includes interval data obtained from month/day/year through month/day/year, where 1045 available. 1046

1047

indication sex age (years) dose (mg/day)

formulation region

male female 2 to ≤16

>16 to 65

>65 unknown

<40 ≥40 unknown

IV oral EU

Japan

Mexico

US/Canada

other

depression

migraine


Table 6 – Cumulative Tabulations of Serious Adverse Events from Clinical Trials 1048

System Organ Class

Preferred Term

[medicinal product]

Blinded Active comparator

Placebo

Investigations n n n n

Alanine aminotransferase increased n n n n

Aspartate aminotransferase increased n n n n

Nervous System Disorders n n n n

Syncope n n n n

Headache n n n n

Table 7 - Numbers of Adverse Drug Reactions by Term from Post-marketing Sources* 1049

Total

interval cumulative interval cumulative interval cumulative interval cumulative cumulative, all

SOC 1MedDRA PT MedDRA PT MedDRA PT

SOC 2MedDRA PT MedDRA PT MedDRA PT MedDRA PT

non-serious**

Non-interventional post-marketing studySpontaneous, including regulatory authority and literature

serious non-serious serious

1050

*Non-interventional studies and spontaneous ICSRs (i.e., reports from healthcare professionals, 1051 consumers, regulatory authorities, and scientific literature) 1052

** Non-serious ADRs from non-interventional Post-Authorisation Safety Studies (PASS) only should be 1053 tabulated here. See Glossary. 1054

1055


APPENDIX C – Tabular summary of safety signals that were new, ongoing 1056 or closed during the reporting interval 1057

Product Name: _________________________________ 1058

Reporting Interval: DD-MMM-YYYY to DD-MMM-YYYY 1059

1060

Signal term

Date detected

Status (new, ongoing or closed)

Date Closed (for closed signals)

Source or trigger of signal

Reason summary

Method of signal evaluation

Outcome, if closed

stroke month/ year

new month/ year

Spontaneous, animal

brief summary of key data and rationale for further evaluation

review cases; epidemiological studies

1061

Explanatory notes 1062

Signal term 1063

A brief descriptive name of a medical concept for the signal. This may evolve and be refined as the 1064 signal is evaluated. The concept and scope may or may not be limited to specific MedDRA term(s), 1065 depending on the source of signal. Where applicable, the table should refer to the specific MedDRA 1066 terms (e.g., PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were reviewed. 1067

• Date detected (month/year) 1068

Month and year when the signal was detected (that is, when a determination was made to conduct 1069 further evaluation). 1070

• Status 1071

New: Signal identified during the reporting interval. 1072

Ongoing: Signal under evaluation at the data lock point (the end of the reporting interval). Provide 1073 anticipated completion date, if known. 1074

Closed: Signal for which evaluation was completed during the reporting interval. 1075

Note: A signal may be “new” and “closed” if an evaluation of a newly identified signal was completed 1076 within the reporting interval. The signal should be identified as “new and closed” in the tabulation, but 1077 handled as a closed signal for the purposes of the evaluation (see Section 3.16.2 of this guideline). 1078

• Date closed (month/year) 1079

Month and year when the signal evaluation was completed. 1080

• Source or trigger of signal 1081


Data or information source from which a signal arose. Examples include, but may not be limited to, 1082 spontaneous adverse event reports, clinical trial data, scientific literature, and non-clinical study 1083 results. 1084

• Reason summary 1085

A brief summary of key data and rationale for further evaluation. 1086

• Outcome, if closed 1087

State whether or not a specific action is required. Refer to the description of signal evaluation (to be 1088 described in the Section 3.16.2 of this guideline, Signal Evaluation) for further detail. Leave blank for 1089 signals under evaluation at the data lock point. 1090

1091


APPENDIX D – List of PBRER sections, identified as providing cumulative or 1092 interval information, and ability to share modules with other regulatory 1093 documents 1094

Cumulative Interval Potential shared module with

1 Introduction X

2 Worldwide Marketing Approval Status X E2F

3 Actions Taken in the Reporting Interval for Safety Reasons

X Parts may be common to E2E and E2F

4 Changes to Reference Safety Information X

5 Estimated Exposure and Use Patterns

5.1 Cumulative Subject Exposure in Clinical Trials X E2E and E2F

5.2 Cumulative and Interval Patient Exposure from Marketing Experience

X X E2E and E2F (cumulative only)

6 Data in Summary Tabulations

6.1 Reference Information Not applicable

Not applicable

6.2 Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials

X E2F

6.3 Cumulative and Interval Summary Tabulations from Post-marketing Data Sources

X X

7 Summaries of Significant Findings from Clinical Trials during the Reporting Period

7.1 Completed Clinical Trials X E2F

7.2 Ongoing Clinical Trials X E2F

7.3 Long-term Follow-up X E2F

7.4 Other Therapeutic Use of Medicinal Product X E2F

7.5 New Safety Data Related to Combination Therapies X E2F

8 Findings from Non-interventional Studies X E2F

9 Information from Other Clinical Trials and Sources X E2F

10 Non-clinical Data X E2F

11 Literature X E2F


12 Other Periodic Reports X

13 Lack of Efficacy in Controlled Clinical Trials X E2F

14 Late-Breaking Information X

E2F, if reports cover same period and submitted at same time

15 Overview of Signals: New, Ongoing, or Closed X§ X

16 Signal and Risk Evaluation

16.1 Summary of Safety Concerns X

16.2 Signal Evaluation X

16.3 Evaluation of Risks and New Information X X

16.4 Characterisation of Risks X

16.5 Effectiveness of Risk Minimisation (if applicable) X

17 Benefit Evaluation

17.1 Important Baseline Efficacy/Effectiveness Information X

17.2 Newly Identified information on Efficacy/ Effectiveness X

17.3 Characterisation of Benefits X X

18 Integrated Benefit-risk Analysis for Approved Indications

18.1 Benefit-risk Context - Medical Need and Important Alternatives

X

18.2 Benefit-risk Analysis Evaluation X

19 Conclusions and Actions X X E2F

20 Appendices to the PBRER

§ At discretion of MAH. 1095

1096


APPENDIX E – Examples of possible sources of information that may be 1097 used in the preparation of the PBRER 1098

Examples of potential sources of information to be used in preparation of a PBRER will be included in 1099 the Step 4 guideline as general guidance. Suggestions for information sources to be included in this 1100 list should be submitted during the consultation period. 1101